Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1
Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1
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DOI：
10.1016/j.yexcr.2006.11.019
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发表时间：
2007-02-15
影响因子：
3.7
通讯作者：
Church, Frank C.
中科院分区：
文献类型：
--
作者：
Beaulieu, Lea M.;Church, Frank C.
活化蛋白C(APC)是一种丝氨酸蛋白酶，通过使凝血因子Va和VIIIa失活来调节凝血酶(IIa)的产生。APC还通过多种机制发挥与炎症、增殖和凋亡相关的非止血作用。以乳腺癌细胞株MDA-MB-231和MDA-MB-435为研究对象，研究了APC在细胞趋化和侵袭中的作用。随着APC浓度的增加(1-50微克/毫升)，细胞的侵袭和趋化作用呈浓度依赖性增加。与3种非活性APC衍生物相比，只有活性形式的APC增加了MDA-MB-231细胞的侵袭力和趋化性。使用改进的“棋盘”分析，APC仅在与细胞一起电镀时影响迁移；因此，APC不是一种化学诱导剂。阻断抗内皮细胞蛋白C受体(EPCR)和蛋白酶激活受体-1(PAR-1)的抗体可减弱APC对MDA-MB-231细胞趋化作用的影响。最后，用增殖抑制剂丁酸钠处理MDA-MB-231细胞，结果表明，APC并不通过增加细胞数量来增加迁移。因此，APC通过与细胞表面结合并通过EPCR和PAR-1激活特定的信号通路来增加细胞的侵袭和趋化能力。(C)2006 Elsevier Inc.保留所有权利。
Activated protein C (APC) is a serine protease that regulates thrombin (IIa) production through inactivation of blood coagulation factors Va and VIIIa. APC also has non-hemostatic functions related to inflammation, proliferation, and apoptosis through various mechanisms. Using two breast cancer cell lines, MDA-MB-231 and MDA-MB-435, we investigated the role of APC in cell chemotaxis and invasion. Treatment of cells with increasing APC concentrations (1-50 mu g,/ml) increased invasion and chemotaxis in a concentration-dependent manner. only the active form of APC increased invasion and chemotaxis of the MDA-MB-231 cells when compared to 3 inactive APC derivatives. Using a modified "checkerboard" analysis, APC was shown to only affect migration when plated with the cells; therefore, APC is not a chemoattractant. Blocking antibodies to endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR-1) attenuated the effects of APC on chemotaxis in the MDA-MB-231 cells. Finally, treatment of the MDA-MB-231 cells with the proliferation inhibitor, Na butyrate, showed that APC did not increase migration by increasing cell number. Therefore, APC increases invasion and chemotaxis of cells by binding to the cell surface and activating specific signaling pathways through EPCR and PAR-1. (c) 2006 Elsevier Inc. All rights reserved.